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Mol. Cell. Biol. doi:10.1128/MCB.01155-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Destabilization of interleukin-6 mRNA requires a putative RNA stem-loop structure, an AU-rich element and the RNA-binding protein AUF1

Swiss Institute for Experimental Cancer Research (ISREC), Genetics Unit, CH-1066 Epalinges, Switzerland

^* To whom correspondence should be addressed. Email: lukas.kuehn{at}isrec.ch.

	Abstract

Interleukin-6 mRNA is unstable and degraded with a half-life of 30 min. Instability determinants can be entirely attributed to the 3'-untranslated region. By grafting segments of this region to stable green fluorescent protein mRNA and subsequent scanning mutagenesis, we have identified two conserved elements, which together account for most of the instability. The first corresponds to a short non-canonical AU-rich element. The other, 80 nucleotides further 5', comprises a sequence predicted to form a stem-loop structure. Neither element alone was sufficient to confer full instability suggesting that they might cooperate. Overexpression of myc-tagged AUF1 p37 and p42 isoforms as well as suppression of endogenous AUF1 by RNAi stabilized interleukin-6 mRNA. Both effects required the AU-rich instability element. Similarly, the proteasome inhibitor MG132 stabilized interleukin-6 mRNA probably through an increase of AUF1 levels. The mRNA co-immunoprecipitated specifically with myc-tagged AUF1 p37 and p42 in cell extracts, but only when the AU-rich instability element was present. These results indicate that AUF1 binds to the AU-rich element in vivo and promotes IL-6 mRNA degradation.

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